BCL-2 family proteins playa major role in the commitment phase of programmed cell death. BCL-2 family proteins contribute either to the onset of cell death or to the protection against cell death. BCL-xL is the major BCL-2 family member expressed in brain, and understanding its function is key to designing strategies for neuroprotectlon. Levels of BCL-xL begin to rise just as synapses are forming in the brain. BCL-xL levels remain high, however, in the adult nervous system even in the absence of a death stimulus, prompting us to hypothesize that BCL-xL plays an important physiological role in synaptic transmission. We have shown that recombinant BCLxL injected into the presynaptic terminal of squid giant ganglion increases the amount of neurotransmitter released upon a stimulus to the synapse. This action of BCL-xL is mimicked by injection of ATP, which occludes the effects of injection of BCL-xL, suggesting that BCL-xL may make more ATP available acutely for synaptic transmission. Furthermore, when BCL-xL is overexpressed in cultured hippocampal neurons, it targets to mitochondria, localizes these organelles to synapses, increases the number and size of synapses and the rate of spontaneous neurotransmitter release events. Short and long term potentiation of neurotransmitter release after high frequency stimulation are well-studied phenomena that occur during development and in neural plasticity. An important form of synaptic plasticity is long term potentiation (L TP) at the CA3-CA 1 synapse in mammalian hippocampus. Changes induced by stimulation at this site are thought to underlie the processes of memory formation. We have strong preliminary evidence to support the hypothesis that BCl[unreadable]xl is required for the modulation of long term potentiation of neurotransmission at this synapse. We hypothesize and have strong evidence that one mechanism of action of BCl[unreadable]xl is to increase the formation and release of ATP by mitochondria. In this application, we will test the concept that inhibition of BCl[unreadable]xl or down regulation of expression of BCl-xl prevents an increase in efficiency of operation of the ATP synthase enzyme complex. We hypothesize that these changes are required for long term changes in synaptic strength after high frequency synaptic stimulation, therefore we plan to test whether inhibition of BCl[unreadable]xl prevents l TP.